A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-C3 in Adult Healthy Volunteers and in Adult Patients With Complement-Mediated Renal Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arrowhead Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

6 May 2024 → 10 Sep 2025

Decision date (initial)

2023-12-07

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Arrowhead Pharmaceuticals Inc.

External identifiers

EU CT number

2023-506690-36-00

ClinicalTrials.gov

NCT05083364

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacodynamic, Others, Pharmacokinetic

To evaluate the safety, tolerability, PK, and PD of multiple doses of ARO-C3 in subjects with complement-mediated renal disease.

Conditions and MedDRA coding

complement-mediated renal disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Able and willing to provide written informed consent prior to the performance of any study-specific procedures
2. Clinical evidence of ongoing disease based on significant proteinuria defined as persistent proteinuria >750 mg/day based on verifiable records and confirmed on a valid 24-hour UPE during Screening
3. Estimated glomerular filtration rate ≥30 mL/min/1.73m2 calculated by Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI) at Screening and currently not on dialysis
4. Must have stable or worsening renal disease, on stable and optimized treatment, in the opinion of the Investigator, for at least 90 days prior to the first dose of ARO-C3 and willing to stay on a stable standard of care regimen for duration of the study; treatments may include, but are not limited to, immunosuppressive agents, anti-hypertensives, and/or anti-proteinurics
5. Subjects must have been on a maximally recommended or tolerated dose of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 90 days prior to receiving first ARO-C3 dose unless contraindicated due to documented intolerance or allergy
6. Vaccinated for N. meningitidis types A, C, W, Y, and B, S. pneumoniae, and Hib within the past 2 years based on source verifiable medical records or willing to receive vaccination 2 weeks prior to administration of the study drug with a meningococcal booster and second pneumococcal vaccine on Day 57. Only subjects who are documented nonresponders to these vaccinations based on verifiable medical records can be exempted from the vaccine requirements per discretion of the PI
7. A negative test result from a coronavirus disease 2019 (COVID-19) polymerase chain reaction (PCR) or other approved test from an appropriate sample (based on local standard of care) during the Screening period OR proof of vaccination with available COVID-19 vaccines based on local vaccine recommendations and guidelines
8. Males or non-pregnant, non-lactating female volunteers 18 to 70 years of age
9. Subjects with a body mass index (BMI) between 18.0 and 35.0 kg/m2, inclusive. Subjects who have a BMI outside of this range may be allowed into the study at the discretion of the Investigator
10. Subjects of childbearing potential must agree to use highly effective contraception in addition to a condom during the study and for at least 90 days following the end of the study or last dose of study drug, whichever is later. Subjects must not donate sperm or eggs during the study and for at least 90 days following the end of the study or last dose of study drug, whichever is later (see Appendix 1 for details). Subjects of childbearing potential on hormonal contraceptives must be stable on the medication for >2 menstrual cycles prior to Day 1.
11. Willing and able to comply with all study visits and study requirements
12. No abnormal finding of clinical relevance at the Screening evaluation that in the opinion of the Investigator could adversely impact subject safety during the study or adversely impact study results
13. Pre-study renal biopsy with source verifiable record confirming diagnosis of C3G within the last 3 years prior to Day 1 (Cohort 7 only) OR confirming IgAN with presence of C3 (Cohort 8 only) within 5 years prior to Day 1.

Exclusion criteria 31

1. Human immunodeficiency virus (HIV) infection, as shown by the presence of anti-HIV antibody (seropositive)
2. Known or suspected hereditary complement deficiency or other primary immunodeficiency syndrome based on medical history
3. Known contraindication or history of anaphylactic reaction to any vaccine or vaccine component or prophylactic antibiotics planned for use in the study
4. Seropositive for hepatitis B virus (hepatitis B surface antigen positive at Screening) or hepatitis C virus (HCV) (HCV antibody positive with reflex confirmation using HCV RNA amplification at Screening). Cured HCV (positive antibody test without detectable HCV RNA) is acceptable if HCV RNA has been negative for at least 2 years
5. Any other medical condition or clinically significant laboratory abnormality at Screening that in the opinion of the Investigator should exclude the subject from participation including known allergy to ingredients in ARO-C3
6. ALT >3×ULN at Screening
7. Platelet count of <100,000 cells/mm3 at Screening
8. Absolute neutrophil count <1000 cells/mm3 at Screening
9. Rapidly progressive glomerulonephritis defined as a 50% reduction in the eGFR within 90 days of Screening or renal biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli
10. Renal biopsy showing interstitial fibrosis/tubular atrophy of more than 50%
11. Monoclonal gammopathy of undetermined significance (MGUS) as confirmed by the measurement of serum free light chains or other investigation as per local standard of care
12. History of major surgery within 90 days of Screening
13. The use of inhibitors of complement factors including ravulizumab, eculizumab, pegcetacoplan, or factor D or B inhibitors within 12 weeks or 5 half-lives (whichever is longer) prior to Screening
14. History of systemic manifestation of IgA disease including Henoch-Schonlein purpura
15. Have used other monoclonal antibody therapies for treatment of IgAN including belimumab within 90 days or rituximab within 180 days of Day 1
16. History of recurrent or chronic infections including infections caused by encapsulated bacterial organisms or viruses including herpes zoster or herpes simplex
17. The presence of fever >38 °C (100.4 °F) or history of an active bacterial, viral, or fungal infection within 14 days prior to treatment administration
18. Uncontrolled hypertension (blood pressure >160/100 mm Hg at Screening)
19. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 beats per minute [bpm] with symptoms), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG. Subjects with a history of atrial arrhythmias should be discussed with the Medical Monitor.
20. Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction <20%, transient ischemic attack, or cerebrovascular accident) within 180 days prior to study entry
21. History of malignancy including multiple myeloma within the last 2 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Subjects with other curatively treated malignancies who have no evidence of metastatic disease and >2-year disease-free interval may be entered following approval by the Medical Monitor
22. History of bone marrow, hematopoietic stem cell, or solid organ (including kidney) transplantation
23. Regular use of alcohol within 30 days prior to the Screening Visit (i.e., more than 14 units of alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol])
24. A 12-lead ECG at Screening with abnormalities that may compromise subject’s safety in this study per Investigator’s discretion, including but not limited to heart block (second degree or higher grade), prolonged QTc (>450 ms by either Bazett or Fredericia correction method), clinically significant atrial arrhythmias, new ST segment elevation or depression, or new Q wave on ECG.
25. Use of an investigational agent or device within 30 days or 5 half-lives (whichever is longer) prior to dosing or current participation in an investigational study
26. Blood donation (500 mL) within 7 days prior to study drug administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the Screening procedures of this study) prior to administration of the study drug as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to study drug administration.
27. Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the subject at additional safety risk
28. History of meningococcal infection
29. History of asplenia (either due to splenectomy or functional asplenia due to underlying systemic disease) or other condition that may predispose to severe infections with encapsulated bacteria
30. History of severe aplastic anemia or concurrent severe aplastic anemia, defined as currently receiving immunosuppressive therapy including but not limited to cyclosporin A, tacrolimus, mycophenolate mofetil or anti-thymocyte globulin
31. History of receiving live or live-attenuated vaccine (e.g., measles-mumps-rubella, yellow fever, and influenza nasal mist) within 1 month prior to the first dose of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence, frequency, and severity of treatment-emergent adverse events (TEAEs)

Secondary endpoints 2

1. Plasma PK of ARO-C3
2. Changes and percent change from baseline in serum complement component (C) 3 (C3) at scheduled visits

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arrowhead Pharmaceuticals Inc.

Sponsor organisation

Arrowhead Pharmaceuticals Inc.

Address

177 East Colorado Boulevard Suite 700

City

Pasadena

Postcode

91105-1976

Country

United States

Scientific contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Shadi Van Trease

Public contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Shadi Van Trease

Third parties 12

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications